Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors |
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| Authors: | Oliveira Fernanda G Sant'Anna Carlos M R Caffarena Ernesto R Dardenne Laurent E Barreiro Eliezer J |
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| Institution: | 1. LASSBio, Laboratório de Avaliação e Síntese de Substãncias Bioativas, Faculdade de Farmácia and Instituto de Química, Universidade Federal do Rio de Janeiro, PO Box 68006, Rio de Janeiro, RJ 21944-910, Brazil;2. Departamento de Química, ICE, Universidade Federal Rural do Rio de Janeiro (UFRRJ), Seropédica, RJ 23851-970, Brazil;3. Programa de Computação Científica—Fundação Oswaldo Cruz (FIOCRUZ/MS)—Manguinhos, RJ 21045-900, Brazil;4. Laboratório Nacional de Computação Científica—LNCC/MCT, Quitandinha, Petrópolis, RJ 25651-075, Brazil;1. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, West Bengal, India;2. Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078, India;1. Biogen Inc., 225 Binney Street, Cambridge, MA 02142, USA;2. Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA;1. Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands;2. University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands;3. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;4. Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, USA;1. Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India;2. Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India;1. Department of Chemistry, Faculty of Art and Sciences, Recep Tayyip Erdogan University, 53100 Rize, Turkey;2. Vocational School of Technical Studies, Department of Chemistry and Chemical Processing Technology, Recep Tayyip Erdogan University, 53100 Rize, Turkey;3. Department of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, 61080 Trabzon, Turkey |
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| Abstract: | In the present work, several computational methodologies were combined to develop a model for the prediction of PDE4B inhibitors' activity. The adequacy of applying the ligand docking approach, keeping the enzyme rigid, to the study of a series of PDE4 inhibitors was confirmed by a previous molecular dynamics analysis of the complete enzyme. An exhaustive docking procedure was performed to identify the most probable binding modes of the ligands to the enzyme, including the active site metal ions and the surrounding structural water molecules. The enzyme-inhibitor interaction enthalpies, refined by using the semiempirical molecular orbital approach, were combined with calculated solvation free energies and entropy considerations in an empirical free energy model that enabled the calculation of binding free energies that correlated very well with experimentally derived binding free energies. Our results indicate that both the inclusion of the structural water molecules close to the ions in the binding site and the use of a free energy model with a quadratic dependency on the ligand free energy of solvation are important aspects to be considered for molecular docking investigations involving the PDE4 enzyme family. |
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